Understanding cell death

Researchers from the Mechanobiology Institute (MBI) at NUS have uncovered insights into what goes on when cells die. Their findings point to epithelial tissues behaving like liquid crystals, and how misalignment in epithelial cells can lead to cell death and extrusion. This was published in the prestigious journal Nature on 13 April.

Epithelial cells line the cavities and surfaces of organs and blood vessels throughout the human body. These are routinely renewed — cells go through a life cycle of their own, eventually dying off to make way for newer, healthier cells. The research team, led by Professor Lim Chwee Teck and Professor Benoit Ladoux, drew inspiration from non-living matter in liquid crystal — which is more commonly familiar to us in display screens — to understand the process of cell death at the cellular level. The NUS team also collaborated with researchers from University of Oxford in the UK, as well as Institut Curie and Institut Jacques Monod in France.

This discovery provides new approaches in controlling, analysing and studying cell growth and death, and offers potential applications in the areas of tissue engineering and regenerative medicine.

— Prof Lim Chwee Teck

Saw Thuan Beng, first author of the research and PhD candidate at NUS, hit upon the idea of investigating epithelial cells as “active” liquid crystals when he was attending a physics lecture during a summer programme in South Korea. “I was looking at the patterns of liquid crystals and noticed that they looked somewhat similar to the cell sheet movement that the team was working on at MBI,” said Thuan Beng.

Studying single-layer epithelial cells in the lab, the team observed that the cells are arranged parallel to one another, with their long sides facing the same direction. As living cells are fluid, their constant movements can lead to their misalignment — also known as topological defects in liquid crystal science — where the arrangement resembles a comet. Through experimental measurements and confirmation by numerical simulations, the cells at the head of the comet pattern were found to experience higher compressive stress than others at the tail. This high stress, concurrently with a combination of a stress-triggered protein and an enzyme, eventually forces the cells to be extruded as dead cells.

Diagram illustrating the process of cell death and extrusion

Prof Lim explained that this new understanding of how cells die is a significant step forward in mechanobiology — a field of study that uses the intersection of biology, physics and engineering to understand living systems. “This discovery provides new approaches in controlling, analysing and studying cell growth and death, and offers potential applications in the areas of tissue engineering and regenerative medicine,” he said.

The team’s findings could also lead to new ways of understanding and tackling cancer. “If cells do not die normally, tissue can pile up and tumours can form. Also, if the tissue fails to eliminate transformed cells, this can lead to cancer. By knowing how cells die and where they die, we can start to understand how cancer may begin at the cellular level,” said Prof Lim. “This new understanding about cell extrusion could perhaps give us new ideas on how we could prevent specific cells from replicating or forcing them to die, as a means to target cancer cells.”

The research team is also excited about the prospect of new research arising from this discovery. They are looking forward to studying how substrate stiffness or electric fields can control cell movement, as well as conduct similar studies with different types of cells, such as a mixed population of cells or with diseased cells.

This discovery also drew enthusiastic views from fellow scientists on the transposition of theories for non-living systems to biological materials. Professor Linda Hirst from the University of California Merced wrote in Nature that “the stage is now set for further discoveries related to active materials in biology, a field of physics that can closely model living systems”.